It was the worst experience of my life. More terrible even than watching my wife die of cancer. I am ashamed to admit that my depression felt worse than her death but it is true. I was in a state that bears no resemblance to anything I had experienced
before. It was not just feeling very low, depressed in the commonly used sense of the word. I was seriously ill. I was totally self-involved, negative and thought about suicide most of the time. I could not think properly,
let alone work, and wanted to remain curled up in bed all day. I could not ride my bicycle or go out on my own. I had panic attacks if left alone. And there were numerous physical symptoms — my whole skin would seem
to be on fire and I developed uncontrollable twitches. Every new physical sign caused extreme anxiety. I was terrified, for example, that I would be unable to urinate. Sleep was impossible without sleeping pills: these
only worked for a few hours, and when I woke up I felt worse. The future was hopeless. I was convinced that I would never work again or recover. There was the strong fear that I might go mad.

I had never been seriously depressed before. On previous occasions the way I dealt with mild depressions — feeling low — was to go jogging. Enquiry among my fellow joggers confirmed my view that we do not exercise for health but to avoid
mild depression. The widely held belief that exercise raises endorphin levels and so provides an uplift in mood turns out to be based on quite reasonable scientific evidence. I have to admit that I then rather sneeringly
proclaimed that I believed in the Sock School of Psychiatry — just pull them up when feeling low. But that certainly does not work with serious depression. The origins and course of my own depression, and my recovery
from it, will be described in later chapters.

My wife, Jill Neville, was embarrassed by my being depressed and told colleagues and friends instead that I was exhausted from a minor heart condition. She was worried that if the truth were known it would affect my career. When I recovered, I was most
uneasy about the stigma associated with depression, and the shame felt by many sufferers; it seemed to me a serious illness of which one should not be ashamed. I therefore decided to make my depression public and wrote
an article about it in the Guardian newspaper. This brought an astonishingly positive response. Patients, doctors and those who had had the experience of living with someone who is
depressed found it helpful to have the subject discussed in so open a manner. Of everything I have written, both books and scientific articles, this article was most widely read and appreciated. When people complimented
me on being so brave, I realised exactly how much stigma is still associated with depression. In fact it was quite easy for me to write about since I had a secure academic position and so nothing to lose.

After I had emerged from my depression I thanked the psychiatrist who had treated me for all her help. I then asked her if I was correct in thinking that psychiatrists really understood nothing about depression. She partly agreed. Of course they have
great skills at diagnosis and treatment; for example, antidepressant drugs like Prozac can bring about remarkable recoveries. But it was at a mechanistic level that little seemed to be known. It was even far from clear
to me what it meant to 'understand' a mental illness, in the same way that one now understands cancer. For example, we can understand cancer in terms of the changes in certain genes involved in the control of
cell multiplication, and also in terms of the spread of the malignant cells. But even if low levels of serotonin, one of the chemicals in the brain linked to depression, were found to be in some way responsible for the
illness, this alone would still be inadequate as an explanation. For how could changes in the concentration in the level of so simple a molecule bring about such profound changes in behaviour as are experienced in depression?

Although there are many 'self-help' books on the subject, I found very little reliable information about depression easily available, and decided to write this book to set down what is known. My purpose is fourfold: to help those who are living
or working with a sufferer to understand the nature of depression, since depressives, whether parents, children or companions, are not easy to be with; to help depressives to understand themselves; to remove the stigma
associated with depression; and, foremost, to try and understand the nature of this dreadful affliction in scientific terms. This last aim is something of a personal quest.

I know that I am entering into areas where I have no direct expertise, being neither a doctor nor a psychologist, but I do have two advantages. I am a research biologist whose interest is in the mechanisms by which embryos develop and the way that genes
control cell behaviour and generate limbs and other organs, so I am familiar with basic biological processes and complex systems. As a scientist I also have some experience of assessing evidence. But more importantly, I
have experienced depression, for anyone who treats or writes about depression and who has not themself been depressed is rather like a dentist who has had no experience of toothache.

Depression is very upsetting not only for the sufferer but for those who live with the victim. Depressives are victims in the sense that they have a frightening and disabling illness; an illness that affects as many as one in ten of the population and
is twice as common in women than in men. Considering how widespread depression is, it is particularly unfortunate that it carries with it the additional burden of severe social stigma.

The effect of depression on health-care services is enormous. A recent report,
Global Burden of Disease, published by the World Health Organisation, states that depression was the fourth most important health problem in the developing world in 1990 (accounting for about 3 per cent of the total
burden of illness) and predicts that it will be the number one health problem in the developing world in 2020 (accounting for about 6 per cent of the total burden). Over the same period the annual number of suicides will
increase from 593,000 to 995,000 in the developing world. The report also estimates that less than 10 per cent of the 83 million episodes of depression in the developing world in 1990 received treatment and that the figure
for treated episodes in developed countries may be only two to three times higher.

Depression has a confusing number of different meanings. In common usage it refers to lowness and anxiety, common feelings in everyday life. But it is depression as an illness with which this book is concerned, depression that so interferes with a person's
life that it is disabling. William Styron's
Darkness Visible is a marvellous description of depression, and at the very start he makes it clear that the 'pain of severe depression is quite unimaginable to those who have not suffered it, and it kills in
many instances because it cannot be borne'. So the focus in this book is on major depression, or, as it is so often called, clinical depression; depression so severe that it can lead to the inability to work or even
to suicide. The relationship between major depression and common everyday depression, just feeling low, is, however, an important one and will be explored: is major depression just an extreme form of common depression or
is it qualitatively different?

My title is in two parts. One comes from Robert Burton's famous, monumental, fascinating, but not easily readable, Anatomy of Melancholy (1621-51) in which he recorded all aspects of the melancholic condition
known at the time. Burton spent most of his life at Christ Church in Oxford where among other duties he taught theology. He had an interest in all branches of medicine and science. He chose to write about Melancholy as
his life's work largely because of his own affliction by it, and he hoped that writing about it would alleviate his symptoms: 'I write of Melancholy, by being busy to avoid Melancholy.' As the choice of Anatomy
for his title implies, he tried methodically to exhaust the topic and cite every known authority. Burton also cared about the style of his writing and would have been gratified had he known that Samuel Johnson, himself
a depressive, turned to the Anatomy for consolation — it was the only book that ever took him out of bed two hours sooner than he wished to rise.

The number of papers published about depression is currently more than 3,000 every year, so I have had to be less ambitious than Burton. The amount of information is enormous, but I try to summarise in an accessible form what is currently known about
depression. I start by looking at the experience of depression in the past and present. Then I look at the problems of diagnosis not only in the West but in other cultures. I try to unravel the factors that make people
vulnerable to depression, such as their genes, distressing life events, early childhood experiences and even the weather. Manic depression, though not central to this book, has its own characteristics, and suicide has to
be recognised as a tragic consequence of depression: I address these subjects in separate chapters. With this background, it becomes possible to discuss the psychological and biological theories that have been put forward
to explain depression, including its evolutionary significance. The psychological explanations focus on the importance of loss and early experience, while the biological require understanding of emotion in terms of brain
function and chemistry. Following this, there are discussions of the treatments for depression, such as medication and psychotherapy, with an analysis of what works and for whom. I also report on experiences in the treatment
of depression in the East — China, Japan and India. Finally I look to the future, both at scientific advances and preventative approaches.

I have been particularly influenced by several books, including William Styron's
Darkness Visible, an account of his own depression; Kay Redfield Jamison's Touched with Fire, which deals with manic depression and creativity as well as other topics related to depression; and The Emotional
Brain by Joseph Le Doux. Several ideas have also been very influential on my approach, particularly John Bowlby's ideas about attachment and loss and Aaron Beck's ideas on the cognitive basis of depression and its relation to negative thinking.
Arthur Kleinman, an anthropologist and a psychiatrist, has illuminated for me the nature of depression in other cultures.

The main title, Malignant Sadness, is meant to emphasise the very serious nature of a depressive illness and also to reflect my conviction that normal sadness is to depression what normal growth is to cancer. I hope
this book will prove interesting and helpful both to those who suffer from depression and to those who live with them.

Chapter One

The Experience of Depression — Past and Present

Until one has experienced a debilitating severe depression it is hard to understand the feelings of those who have it. Severe depression borders on being beyond description: it is not just feeling much lower than usual. It is a quite different state,
a state that bears only a tangential resemblance to normal emotion. It deserves some new and special word of its own, a word that would somehow encapsulate both the pain and the conviction that no remedy will ever come.
We certainly could do with a better word for this illness than one with the mere common connotation of being 'down'.

Major or severe depression, also known as clinical depression because it is disabling, should be distinguished from a milder depressed mood. For some sufferers the main feeling is an over-whelming sadness which can be accompanied by numbness, dullness
and apathy: thoughts of suicide are common, as are crying spells. Yet others can become very irritable, even angry. Difficulties with sleeping are common too, as are fatigue and a lack of energy. In severe cases the patient
can hardly move and is almost comatose, and may experience hallucinations and delusions. Almost always there is also an inability to concentrate for long or to make decisions. There may be a general feeling of hopelessness
coupled with a loss of self-esteem. Often anxiety is the dominant emotion and this may lead to hypochondria — excessive worries about one's health, each apparently abnormal bodily symptom being interpreted as
evidence of a major illness. A characteristic feature of depression is the loss of interest or pleasure in almost all activities. Even when something good happens the depressed mood does not improve. It is also characteristic
that the depression is worst in the morning and associated with early morning awakenings.

The terms melancholy and depression are closely related and melancholy is the term that was usually used to describe the condition until quite recently. But while the term depression to describe a mental condition is often thought of as having a modern
origin, it was actually used in 1665 in Baker's
Chronicle, which referred to someone having 'a great depression of spirit'. It is also used in a similar sense by Samuel Johnson in 1753, and George Eliot in Daniel Deronda writes, 'He found
her in a state of deep depression'. Yet, as William Styron so brilliantly puts it, depression is a word 'that has slithered through the language like a slug, leaving little trace of its intrinsic malevolence and
preventing by its very insipidity, a general awareness of the horrible intensity of the disease when out of control'.

The clinical features of depression are well described by one of the pioneers of its study, the German psychiatrist Emil Kraepelin, writing in 1921:

He feels solitary, indescribably unhappy, as a "creature disinherited of fate"; he is skeptical about God, and with a certain dull submission, which shuts out every comfort and every gleam of light, he drags himself with difficulty from one
day to another. Everything has become disagreeable to him; everything wearies him, company, music, travel, his professional work. Everywhere he sees only the dark side and difficulties; the people around him are not so
good and unselfish as he thought; one disappointment and disillusionment follows another. Life appears to him to be aimless, he thinks that he is superfluous to the world, he cannot constrain himself any longer, the thought
occurs to him to take his life without knowing why. He has a feeling as if something has cracked in him.

There is nevertheless something absurd about the depressive state, for the feelings and thoughts of the depressive can bear so little relation to reality. Some of these almost ridiculous features are described by the writer Andrew Solomon in an article
for The New Yorker. He describes lying in bed too frightened to take a shower. While he could mentally rehearse all the steps that were required to get him to the shower, they became
like 14 steps as painful and difficult as the Stations of the Cross. Even though he knew that he had effortlessly showered every day for years he now hoped that someone else would open the bathroom door. It all seemed so
idiotic and hopeless, particularly as he had done skydiving, and it seemed that it had been easier to make his way toward the tip of a plane's wing against a powerful wind at 6,000 feet than it was now to get out of
bed and take a shower. No wonder that he wept.

If we had a soul — and as a hardline materialist I do not believe we do — a useful metaphor for depression could be 'soul loss' due to extreme sadness. The body and mind emptied of the soul lose interest in almost everything except
themselves. The idea of the wandering soul is widely accepted across numerous cultures and the adjective 'empty' is viewed across most cultures as negative. The metaphor captures the way in which we experience
our own existence. Our 'soul' is our inner essence, something distinctly different from the hard material world in which we live. Lose it and we are depressed, cut off, alone.

Depression, or melancholy as it was known, has a long history, probably as long as that of Homo sapiens itself, and there are descriptions going back to the earliest literature. It is present in the Bible. Listen
to Job's despair: 'Why is light given to those in misery, and life to the bitter of soul, to those who long for death that does not come, who search for it more than for hidden treasure, who are filled with gladness
and rejoice when they reach the grave?' (Job 3:20-22)

It was, and still is, common in various cultures to attribute the cause of mental illness to a supernatural agent. In Ancient Greece it was believed that mental illness could be inflicted by the gods as a punishment for some misdeed. In early Christian
times it was sometimes considered to be a test of the faithful, sent by the Devil. Melancholia as a distinct medical condition was, however, already recognised in Greece in the 4th century BC in the Hippocratic writings.
It was associated with aversion to food, despondency, irritability and restlessness and fear. The leading authority on medical conditions in the 2nd century BC was Galen, whose humoral theory lasted for centuries to come.
The explanation for the condition was in terms of an imbalance of the four Galenic humours — blood, yellow bile, black bile and phlegm — that were thought to govern human well-being and illness. Melancholia
was thought to be due to an excess of black bile. Galen's description of the condition has a contemporary ring: 'Although each melancholic patient acts quite differently than the others, all of them seem to be
filled with fear or despondency. They find fault with life and hate people but not all want to die...Others again will appear to you quite bizarre because they dread death and desire to die at the same time.'

It is somewhat ironic that in earlier times there was not always the stigma attached to depression that there is today, and that the melancholic thought of himself as a rather superior being. For Aristotle, melancholy was the temperament of the creative
artist, for creativity was thought to be driven by black bile. Aristotle had an influence on attitudes to melancholy that lasted for centuries, since he asked why it was that those who became eminent in philosophy, politics,
poetry or the arts, as well as many of the great Greek heroes, were of a melancholic temperament. He included among these Plato and Socrates. There could be, he suggested, a touch of mad genius in melancholia, and so melancholy
was an enviable condition of the mind.

By the late 4th century the Christian Church was using the term to refer to 'a weariness or distress of the heart' — a condition that was regarded as undesirable and requiring treatment. While initially associated with sadness it later
became associated with the 'sin of sloth' and known as accidie. Accidie in the 1300s was listed by the church as a cardinal sin for it made, for example, monks lazy and sluggish. For St Thomas Aquinas, accidie
was the result of shrinking from doing some good. But the concept of accidie is more complex than that, and interpretations vary. Some commentators related the origin of black bile to Adam's eating of the forbidden
apple. With the weakening of the power of the Christian Church in the 15th and 16th centuries accidie became more and more associated with melancholia.

An Arabic medical writer in Baghdad in the early 10th century wrote a treatise on melancholia claiming that black bile was its immediate cause. His definition of the illness is striking: 'A certain feeling of dejection and isolation which forms in
the should because of something that the patients think is real but which is in fact unreal.' He describes those afflicted as 'sunk in an irrational, constant sadness and dejection, in anxiety and brooding'.
He attributed mental overexertion as a major cause of the condition, but also recognised the role of bereavement and loss of possessions.

Paracelsus, a leading medical writer in the Renaissance regarded melancholy as a form of insanity. His suggestion as to how it should be cured — 'If a melancholic patient is despondent make him well again with gay medicine' — is
alas, quite the wrong way to proceed. The term melancholy as used in the scientific literature of the time referred to a cold dry humour normally present in the body. This natural melancholy could be corrupted by heat and
so form a noxious humour. The term melancholic could also denote a person in whom black bile was dominant and could cause physical infirmities, fear and sorrow. This condition could worsen to give rise to a mental disorder
with excessive sadness and fears, lethargy and a dislike of humankind. An improper diet was often thought to be the cause. Bloodletting to eliminate the offending humour, and warm, moist air and mental diversion, were strongly
recommended.

The idea of melancholy began to appear frequently in English literature in the 1580s and the word was in common use in England during the Renaissance. In contrast to the medical perception of melancholy, Aristotle's view persisted, and Robert Burton,
for example, asserted that 'melancholy men are of all other the most witty'. It was thought that melancholy encouraged intellectual and creative talents. Yet Hamlet with his black clothing and lack of sociability,
his morose brooding and suicidal thoughts, would also have been totally consistent with the Elizabethan conception of a melancholic man:

I have of late (but wherefore I know not) lost all my mirth, foregone all custom of exercises; and, indeed, it goes so heavily with my disposition, that this goodly frame, the earth, seems to me a sterile promontory; this most excellent canopy, the air,
look you, — this brave o'erhanging firmament, this majestical roof fretted with golden fire, — why, it appears no other thing to me than a foul and pestilent congregation of vapours.

There were several treatises that could well have had an influence on Shakespeare. A Discourse...of Melancholicke Disease by du Laurens was typical and described the sadness of the melancholic and the fitfulness
of their sleep; sadness without cause was a common description. In Burton's Anatomy of
Melancholy, humoral theory remained central. His description included many physical disorders such as headache, bellyache and palpitations, and there is little reference to guilt. While he recognised grief associated with bereavement as a possible
cause of melancholy he complained of the confusions and contradictions in deciding just what melancholy is. As a working definition he chose 'a kind of dotage, without a fever, having for his companions fear, and sadness,
without any apparent occasion'. 'Never despair,' he counselled the melancholic. 'It may be hard to cure but not impossible for him, that is most grievously affected, if he but be willing to be helped.'
He advised the use of prayers and 'physic'.

By the late 17th century the humoral explanations of Galen were giving way to chemical and mechanical ones. The latter particularly gained pre-eminence in the 18th century, influenced by a Newtonian, mechanical view of the world. Thus, for example, Harvey's
discovery of the circulation of the blood led to theories which were based on a faulty circulation, and these then gave way to theories that emphasised the electrical properties of the brain. But, as in the 17th century,
treatment was still largely Galenic — bloodletting, cathartics and emetics were used to drain the body of the black, melancholic humour.

In 1691 Timothy Rogers wrote a book about his own melancholy which was for him 'the worst of all Distemper; these sinking and guilty fears which it brings along with it, are inexpressibly dreadful'. He often felt that God had departed from his
soul and he frequently contemplated suicide. In 1733, an Edinburgh doctor, George Cheyne, himself a depressive, wrote of the 'English Malady', by which he was referring mainly to those with a 'deep and fixed
melancholy', a condition he ascribed to at least a quarter of the middle and upper classes. Another author, William Cowper, in 1773 was 'plunged into a melancholy that made me almost an infant' and he too
thought of himself as 'deserted by God'. John Donne wrote in the 17th century that 'God has accompanied, and complicated almost all our bodily diseases of these times, with an extraordinary sadness, a predominant
melancholy, a faintnesse of heart, a cheerlessness, a joylessness of spirit'; this view of melancholy persisted until late in the 18th century when there was a change in medical perceptions, and mental disorders were
seen as a disorder in the brain rather than the blood or the soul.

Patterns of negative feeling are very common characteristics of depressed people. In this state, the recall of pleasant experiences is difficult. John Stuart Mill records in his autobiography the experience of such negative thoughts and the inability
to enjoy anything:

In this frame of mind it occurred to me to put the question directly to myself, 'Suppose that all your objects in life were realized; that all the changes in institutions and opinions which you are looking forward to, could be completely effected
at this very instant: would this be a great joy and happiness to you?' And an irrepressible self consciousness distinctly answered, 'No!' At this my heart sank within me: the whole foundation on which my
life was constructed fell down. All my happiness was to have been found in the continual pursuit of this end. The end had ceased to charm, and how could there ever again be any interest in the means? I seemed to have nothing
left to live for.

At first I hoped that the cloud would pass away of itself; but it did not. A night's sleep, the sovereign remedy for the smaller vexations of life, had no effect on it. I awoke to a renewed consciousness of the woeful fact. I carried it with me into
all companies, into all occupations. Hardly anything had power to cause me even a few minutes oblivion of it. For some months the cloud seemed to grow thicker and thicker. The lines in Coleridge's 'Dejection'
— I was not then acquainted with them — exactly describe my case:

A grief without a pang, void, dark and drear, A drowsy, stifled, unimpassioned grief, Which, finds no natural outlet or relief In word, or sigh, or tear.

In vain I sought relief from my favourite books; those memorials of past nobleness and greatness, from which I had always hitherto drawn strength and animation.

Considering how widespread depression is, there are few descriptions in the English novel. Suggestions, for example, that Lucy Snowe in Charlotte Brontë's Villette and Pip in Dickens' Great Expectations suffer from depression are misleading, for in both cases, while the characters are on occasion very unhappy, that is a long way from depression. Perhaps depression is so negative a condition that authors have avoided describing
it. Nevertheless, the absence in novels is made up for by poets' and authors' descriptions of their own depressions. Gerard Manley Hopkins' poem is a disturbing description of the pain of depression:

No worst, there is none. Pitched past pitch of grief, More pangs will, schooled at forepangs, wilder wring. Comforter, where, where is your comforting? Mary, mother of us, where is your relief? My cries
heave, herds-long; huddle in a main, a chief- Woe, world-sorrow; on an age-old anvil wince and sing- Then lull, then leave off. Fury had shrieked 'No ling- Ering! Let me be fell: force I must be brief'. O the mind, mind has mountains; cliffs of fall Frightful, sheer, no-man-fathomed. Hold them cheap May who ne'er hung there. Nor does long our small Durance deal with that steep or deep. Here! creep, Wretch, under a comfort serves in a whirlwind: all Life death does end and each day dies with sleep.

The French poet Gérard Nerval used the metaphor of the black sun to sum up the blinding force of depression in his poem 'The Disinherited', which starts with the lines:

The mood of misery and suffering that usually accompanies depression was expressed by Edgar Allan Poe in a letter written when he was in his mid-twenties:

My feelings at this moment are pitiable indeed. I am suffering under a depression of spirits such as I have never felt before. I have struggled in vain against the influence of this melancholy — You will believe me when I say that I am still miserable
in spite of the great improvement in my circumstances. I say you will believe me, and for this simple reason, that a man who is writing for effect does not write thus. My heart is open before you — if it be worth
reading, read it. I am wretched, and know not why. Console me — for you can. But let it be quickly — or it will be too late. Write me immediately. Convince me that it is worth one's while — that
it is at all necessary to live, and you will prove yourself indeed my friend. Persuade me to do what is right. I do not mean this — I do not mean that you should consider what I now write you a jest — oh pity
me! for I feel that my words are incoherent — but I will recover myself. You will not fail to see that I am suffering under a depression of spirits which will [not fail to] ruin me should it be long continued.

Another account comes from the contemporary neuroscientist George Gray who had a severe depression in his fifties and describes the course of the illness in terms of the inability to anticipate future pleasant events, which he calls self-grooming.

In the early stages he begins to feel physically ill, and as the days pass his mental self-grooming decreases. At the start his optimism prevails. 'I feel ill now and unable to cope, but tomorrow I'll feel better.' When tomorrow arrives,
however, and he feels slightly worse, he learns that the optimism of the previous day was unjustified. This gradual unlearning of optimism continues on for hundreds, even thousands of days, all optimistic thought abolished
— for the patient has learned (correctly) that the future holds nothing but terrible suffering. Mental self-grooming has ceased and day after day a thousand and one events confirm previous pessimistic thoughts and
a complete breakdown results.

These descriptions might provide some small sense of what it is like to be depressed even though severe depression is virtually indescribable to anyone who has not experienced it. But it is essentially a Western view of depression and gives no clue as
to how depression is experienced in other cultures. Depression can be experienced in different ways and in some cultures physical symptoms such as headaches and stomach pains can be dominant. Such differences raise the
issue as to whether depression has features common to all cultures and is indeed a single disease.

There is another aspect to the experience of depression that is of the greatest importance but very often neglected; the effect of depression on those associated with a depressed individual. There are very few descriptions of the tribulations suffered
by carers. For the carer it is often extremely difficult to understand why their partner, for example, should be in this condition, particularly when there are no obvious reasons for it — after all, we are all beset
at some time or another by difficult problems and it can seem that the depressed person is just not trying hard enough. But trying to push someone out of depression or to persuade them to snap out of it does not work. While
marriage can help to protect against depression, as can any close and intimate relationship, depression can put a great strain on such relationships. Marital conflict and the absence of support can cause a worsening of
the condition. Moreover, life with a depressed person can make a partner angry, and many have to seek psychological help to deal with the situation.

In an experimental study subjects were asked to speak on a telephone with a patient who, unknown to the subjects, was depressed. When asked about their conversations their reports were very negative. Other studies have confirmed that depressed individuals
have a negative impact on those with whom they interact. When in a position of power depressives tend to exploit their position and can be uncooperative. In low power roles they tend to blame others. I recall with some
guilt that long before I had my depressive experience I had employed an assistant in the laboratory on a temporary basis. She was very good at her work but at the border of a severe depression. Her effect on the group in
the laboratory was so bad that they had great difficulty working not only with her but even near her and so I decided she could not continue.

The serious nature of depressive illness as experienced by sufferers is evident. I now turn to the medical viewpoint: how can it be diagnosed?